Of the four million babies born in the USA each year: 1 in 8 is born prematurely. Respiratory distress syndrome (RDS) and it's sequelae, contribute significantly to 1,140 of the 5,520 deaths each year due to complications of prematurity. Despite the significant strides that have been made in neonatal intensive care, the consequences of RDS have not been significantly altered. Since a cure for premature delivery has not been accomplished to date, investigators have focused on ways to enhance lung maturation. Vascular endothelial cell growth factor (VEGF) is an important regulator of vascular development and lung maturation. The effects of VEGF in the developing lung and the mechanisms of these effector responses, however, have no been described. To define the effects of VEGF we used a novel, inducible, overexpression transgenic system in which transgenes can be selectively targeted to the lung and activated in utero, in neonates or in adult animals. When VEGF was overexpressed in the adult respiratory tract, a complex phenotype was noted that included heightened bronchial and parenchymal angiogenesis, mononuclear inflammation, and an impressive survival advantage in the setting of 100% oxygen exposure. These alterations were associated with significant increase in total lung phospholipids and an increase in surfactant protein (SP)-B and C but not A or D. Interestingly, nitric oxide (NO)-dependent pathways were responsible for the vascular and survival effects but not the effects of VEGF on alveolar maturation. When VEGF was selectively expressed in the neonatal lung, enhanced lung maturation was also appreciated. In contrast to what was seen in the adult, however, VEGF expression was associated with enhanced hyperoxic acute lung injury (HALI). As a result of these findings we have generated the following hypotheses: 1) VEGF is a pivotal mediator of vascular and alveolar maturation in the murine lung. 2) VEGF, while enhancing lung maturation, simultaneously enhances respiratory susceptibility to HALI in the developing lung 3) The effects of VEGF are mediated by NO-dependent and -independent pathways with enhanced HALI being mediated by the former and enhanced lung maturation being mediated via the latter. If our hypotheses are correct: this would suggest that an optimal VEGF-based intervention to enhance lung maturation would be VEGF in combination with an NO inhibitor. To test these hypotheses, we propose to: 1) Define the effects of VEGF on vascular and alveolar development in the fetal and newborn (NB) lung. 2) Define the role(s) of NO, and understand the mechanism of the NO pathway in the pathogenesis of the vascular and alveolar effects of VEGF in the fetal and NB lung. 3) Characterize the effects of, and understand the mechanism(s) of antenatal VEGF activation and/or NO in the fetal lung exposed to hyperoxia.